The condition of "dry eye" results from diminished production of the aqueous tear component. Some forms of dry eye are age-related and more common in females. Other manifestations of dry eye are associated with inflammatory disorders such as rheumatoid arthritis and Sjogren's syndrome. In rare cases there is a congenital absence of the lacrimal gland. Regardless of the etiology, in severe cases the absence of lubrication to the cornea can result in ulceration and blindness. The frequency of occurrence of dry eye means that it is a significant public health problem. Despite our long-standing knowledge of the dry eye condition and its potentially severe consequences, study of lacrimal gland development using techniques of modern molecular genetics has only recently been initiated. These studies took advantage of a transgene reporter that marked the epithelial component of the gland and allowed us to easily follow the process of budding and branching that occurs during development of the gland. Ultimately, this work showed that both the transcription factor Pax6 (expressed in gland epithelium) and the growth factor FGF10 (expressed in periorbital mesenchyme) were required for normal lacrimal gland development. With the current proposal, it is our intention to build on these studies and examine the role of the transcription factor Barx2, the bone morphogenetic proteins 4 and 7 and the adhesion molecule Ng-CAM in gland morphogenesis. The Specific Aims include (1) an examination of whether an FGF1O gradient is a controlling factor in gland morphogenesis, (2) a determination of how BMPs 4 and 7 can influence lacrimal gland morphogenesis, (3) loss-of-function experiments to determine whether the transcription factor Barx2 is required for gland morphogenesis, (4) an assessment of whether there is a regulatory relationship between Barx2 and the BMPs, and (5) a determination of whether Barx2 regulates the expression of the adhesion molecule LI. Combined, these will provide a focussed effort designed to answer questions central to the mechanism of lacrimal gland development and may provide an understanding of how to approach treatment of the dry eye condition.